Comparative effectiveness of ultrathin vs. standard strut drug-eluting stents: insights from a large-scale meta-analysis with extended follow-up

Background Newer generation ultrathin strut stents are associated with less incidence of target lesion failure (TLF) in patients undergoing percutaneous coronary intervention (PCI) in the short term. However, its long-term effect on different cardiovascular outcomes remains unknown. Objectives We aim to identify the effects of newer-generation ultrathin-strut stents vs. standard thickness second-generation drug-eluting stents (DES) on long-term outcomes of revascularization in coronary artery disease. Methods We searched PubMed, Web of Science, Cochrane Library databases, and Scopus for randomized controlled trials (RCTs) and registries that compare newer-generation ultrathin-strut (< 70 mm) with thicker strut (> 70 mm) DES to evaluate cardioprotective effects over a period of up to 5 years. Primary outcome was TLF, a composite of cardiac death, target vessel myocardial infarction (TVMI) or target lesion revascularization (TLR). Secondary outcomes included the components of TLF, stent thrombosis (ST), and all-cause death were pooled as the standardized mean difference between the two groups from baseline to endpoint. Results We included 19 RCTs and two prospective registries (103,101 patients) in this analysis. The overall effect on the primary outcome was in favor of second-generation ultrathin struts stents in terms of TLF at ≥ 1 year, ≥ 2 years, and ≥ 3 years (P value = 0.01, 95% CI [0.75, 0.96]), P value = 0.003, 95% CI [0.77, 0.95]), P value = 0.007, 95% CI [0.76, 0.96]), respectively. However, there was no reported benefit in terms of TLF when we compared the two groups at ≥ 5 years (P value = 0.21), 95% CI [0.85, 1.04]). Some of the reported components of the primary and secondary outcomes, such as TLR, target vessel revascularization (TVR), and TVMI, showed the same pattern as the TLF outcome. Conclusion Ultrathin-strut DES showed a beneficial effect over thicker strut stents for up to 3 years. However, at the 5-year follow-up, the ultrathin strut did not differ in terms of TLF, TLR, TVR, and TVMI compared with standard-thickness DES, with similar risks of patient-oriented composite endpoint (POCE), MI, ST, cardiac death, and all-cause mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-024-01949-7.


Introduction
Percutaneous coronary intervention (PCI) is the recommended revascularization approach for restoring blood flow to the heart in patients with stable coronary artery disease (SCAD) when medical treatment fails to enhance prognosis or alleviate symptoms (chest pain, weakness, short of breath) [1].Additionally, it is the recommended reperfusion strategy for patients presenting with acute ST-segment elevation myocardial infarction (STEMI) [2].The implementation of first-generation drug-eluting stents (DES) decreased the occurrence of restenosis compared to bare metal stents.However, this advancement was at the expense of higher rates of stent thrombosis (ST).The incidence of definite very late ST ranges from 0.6 to 0.7% per year, while the rate of major adverse cardiac events (MACE) showed a steady increase of 2.6% annually [3].The occurrence of unfavorable outcomes with the first-generation and contemporary permanent polymer-based DES provides a chance for step-by-step enhancement [4][5][6][7][8][9].
Improved stent design, enhanced polymer coating, and the rate of release of antiproliferative agents have contributed to DES's increased safety and efficacy.Secondgeneration thin-strut DES have demonstrated a reduced risk of restenosis, ST, myocardial infarction (MI), or even death compared to older-generation DES or bare metal stents [10,11].Additionally, newer generations of stents with ultrathin strut thickness or biodegradable polymers can accelerate endothelialization, enhance healing, reduce inflammation and arterial injury, and decrease neointimal proliferation and thrombogenicity [12].
Recent research showed that ultrathin-strut DES with a thickness of less than 70 µm can enhance outcomes even more than second-generation DES [13].Ultrathin second-generation DES has been found to have lower rates of target lesion failure (TLF) at both 2 years and 3 years compared to second-generation DES with standard thickness, as demonstrated by a recent meta-analysis [14].Nevertheless, the long-term safety and efficacy of the initial advantages granted by ultrathin second-generation DES is still unknown.Hence, we conducted an updated systematic review and meta-analysis, with an extended follow-up period of 5 years, to compare the clinical outcomes between ultrathin-strut and standard thickness second-generation DES.

Data collection and extraction
We searched PubMed, Scopus, Web of Science, and Cochrane Library databases up to November 2023 using the search terms: (Ultrathin strut OR Thin strut OR Orsiro stent) AND (Sirolimus-eluting stent OR SES OR drug-eluting stents OR DES) AND (Coronary artery intervention OR Percutaneous coronary intervention OR Coronary angioplasty OR Stent implantation).
Endnote software (Clarivate Analytics, PA, USA) removed duplicates.The retrieved references were screened in two steps: the first consisted of screening the titles/abstracts independently by (A.M, M.N, and A.H) to determine their relevance, and the second consisted of screening the full-text articles of the identified abstracts for final eligibility to the quantitative analysis.The Rayyan website was used in the selection process [15].
Our search identified 994 results after duplicates were removed.Following the title and abstract screening, 53 papers were selected for full-text review.Of them, 50 studies were included in the meta-analysis.No further papers were included after manually searching the references of the included studies.The selection process is illustrated in the PRISMA flow diagram of the study in Fig. 1 and was registered on PROSPERO (CRD42024506460).
Studies enrolled patients with coronary artery disease undergoing PCI, comparing ultrathin sirolimus-eluting stent vs. standard thickness second-generation DES in RCTs, and registries reporting clinical outcomes were included in our meta-analysis.Animal studies, non-English studies, abstracts without available data, and unpublished studies were excluded.The data were extracted to a uniform standardized data extraction sheet, including (1) a summary of study characteristics, (2) stent characteristics, (3) baseline patient characteristics, (4) lesion characteristics and treatment procedures, and (5) clinical outcomes.

Outcomes
The primary endpoints of the current analysis included TLF, a composite of cardiac death, target vessel myocardial infarction (TVMI), and target lesion revascularization (TLR).Secondary outcomes included patient-oriented composite endpoint (POCE) of all-cause death, MI, repeat revascularization, and each component of TLF and ST.All outcomes are up to 5 years of follow-up.

Risk-of-bias assessment
We utilized the revised Cochrane risk-of-bias tool for RCTs (RoB 2) to evaluate the risk of bias in the included clinical trials [16].This evaluation encompassed an assessment of the randomization process, concealment of the allocation sequence, deviations from the intended interventions, utilization of appropriate analysis to estimate the effect of assignment to intervention, measurement of the outcome, selection of the reported results, and overall risk of bias.The assessment of the methodological quality of the studies was classified as either low risk, with some concerns, or high risk of bias.For prospective registries, we used The Cochrane ROBINS-I tool [17], which includes the following domains:

Statistical analysis
We used RevMan v5.3 to conduct the statistical analysis [18].We used the risk ratio (RR) to pool the results of dichotomous outcomes, and we used the mean difference (MD) with a 95% confidence interval (CI) to pool the continuous outcomes.We used the fixed-effects model.However, the random-effects model was used in case of significant heterogeneity.Chi-square and I-square tests were used to evaluate heterogeneity, where the Chi-square test detects the presence of heterogeneity, and the I-square test evaluates its degree.I-square was interpreted in accordance with the Cochrane Handbook (chapter nine) [19] as follows: heterogeneity is not significant for 0-40%, moderate for 30-60%, substantial for 50-90%, and considerable for 75-100%.We considered an alpha level below 0.1 for the Chi-square test to detect significant heterogeneity.We performed a leaveone-out sensitivity analysis to address the heterogeneity in our pooled studies.By systematically excluding each study one at a time, we identified which studies contributed to the heterogeneity and reported our findings accordingly.We used Stata MP version 17 (Stata Corp) to assess the publication bias by inspection and Egger's test in outcomes reported by ten or more studies.We conducted a subgroup analysis for the follow-up duration as follows: ≥ 1 year (any study's follow-up duration from 1 year to less than 2 years), ≥ 2 years (any study's followup duration from 2 years to less than 3 years), ≥ 3 years (any study's follow-up duration from 3 years to less than 4 years), and ≥ 5 years (any study's follow-up duration 5 years or more).
We conducted a subgroup analysis comparing acute coronary syndrome (ACS) and chronic coronary syndrome (CCS) patients for all available outcomes across all follow-up durations.We detected a subgroup difference using the test of subgroup difference.

Results
After a detailed search, 19 RCTs and two registries were included in our meta-analysis , according to the Cochrane RoB2 and ROBINS-1 assessments.Nine studies had an overall low risk of bias, 11 had some concerns, and one had an overall high risk of bias (Fig. 2).Analysis of publication bias is summarized in Supplementary Table 3.

Characteristics of the included studies
These studies included 103,101 patients who underwent PCI for coronary artery disease (for both CCS and ACS) using ultrathin-struts DES, n = 19,001; standard thickness second-generation DES, n = 84,100).Nine studies have reached five 5-year follow-ups, five studies have reached three 5-year follow-ups, three studies have reached 2-year follow-ups, and 4 years have reached 1-year follow-ups.The details of studies characteristics are presented in Table S2.Summary of stent characteristics, baseline patient characteristics, lesion characteristics, and intervention procedures of the are outlined in Tables 1, 2, and 3.

Target vessel-related myocardial infarction (TVMI)
Ultrathin-struts DES were associated with a decreased incidence of TVMI at ≥ 2 years (RR: 0.81 with 95% CI [0.68, 0.97], P = 0.02) compared to standard thickness               2. At 1 and 2 years, ultrathin-struts DES showed a considerably decreased incidence of TLR compared to standard thickness second-generation DES.However, there is no significant difference in TLR between the two types of stents after 3 and 5 years.3.No significant difference was noted between the two groups in terms of all secondary outcomes, except for TVR.The occurrence of TVR was lower in the ultrathin group during the initial 3-year period when compared with the group using thicker DES; nevertheless, this discrepancy disappeared at 5 years.

Effect on outcomes components
One of the important components of the primary clinical outcomes is the TLF, which includes restenosis, thrombosis, and revascularization in the treated artery.
In our study, an ultrathin stent was associated with a lower incidence of TLF at 1, 2, 3 years, which could represent an early advantage and may be related to the short and intermediate-term effect of the ultrathin strut's stents.On the other hand, at 5 years, the difference in TLF between the two types of stents was not noticeable, raising concerns about the long-term durability.
The positive effect of ultrathin stent in reducing the short and intermediate-term TLF may be attributable to the stent design.Ultrathin-struts DES have a unique design that differentiates them from the standardthickness second-generation DES.The ultrathin strut design, measuring 60 µm, outperforms existing stents like XIENCE (81 µm) (Abbott Vascular, Santa Clara, CA) and RESOLUTE (91 µm) (Medtronic, Santa Rosa, CA, USA) in terms of flexibility and deliverability.This design reduces endothelial trauma, promoting excellent endothelial coverage and decreasing perivascular inflammation, resulting in a healthier vascular environment [70].The ultrathin-strut DES evaluated in this meta-analysis has a similar metallic stent platform strut thickness and uses biodegradable polymers.They differ, however, in some elements of DES design, such as stent platform geometry, polymer composition, distribution or degradation time, and the kinetics of the antiproliferative medication delivered [12,70].Furthermore, characteristics inherent in the design, such as stent conformability and deliverability, can influence clinical outcomes in individuals with acute coronary syndromes (ACS), which offer a higher long-term sensitivity to stent-related adverse events.This is principally due to an enhanced prothrombotic and inflammatory response following the insertion of DES, leading to a delay in the healing process in the artery region where the stent is present [71].Furthermore, the ultrathin design reduces side branch coverage even further, especially in vessels less than 3 mm in
The details of primary and secondary outcome results are presented in Table 4.
TLF subgroup analysis regarding ACS versus CCS patients, there was no significant difference between ultrathin-struts DES and standard thickness second-generation DES at 1 year, 2 years, 3 years, and 5 years followup (P values for the subgroup analysis were 0.48, 0.97, 0.32, 0.63 consecutively) (Figures S31A-S31D).
More details about heterogeneity and sensitivity analysis are provided in the supplementary material.

Discussion
In this systematic review and meta-analysis, which included 103,101 patients from 21 studies with 1-to 5-year follow-ups, we compared the safety and efficacy of ultrathin-struts DES to standard thickness second-generation DES, and we elucidated that 1. ultrathin struts have a lower incidence of TLF after 1, 2, and 3 years.Nevertheless, this benefit fades 5 years, with no noticeable difference.diameter, minimizing the risk of periprocedural myocardial infarction and, as a result, the incidence of TVMI [71].
The lack of a significant difference in all-cause mortality or even cardiac death between ultrathin DES and standard-thickness DES could be attributed to other contributing factors than the stent design, such as clinical, anatomical, and local pathophysiological lesion characteristics.
The findings of this study are consistent with previous research [13,71,72], showing that even minor changes in strut thickness, ranging from 20 to 30 mm, may be sufficient to produce unique stent-related outcomes in newergeneration DES in routine clinical settings.Our study's effect on TLF aligns with the results of previously published meta-analyses [14,[72][73][74] except for Li et al., 2023 which showed no difference, and a smaller sample size can explain this.Our study is the first meta-analysis to compare the two groups regarding POCE and reported revascularization, and it showed no statistically significant difference between the two groups.Our results align with the previous meta-analyses [14,[72][73][74], which showed no statistically significant difference in all-cause mortality, cardiac mortality, and definite or probable ST outcomes.
Notably, while ultrathin-strut stents showed promising effects in the short term, their benefits may not be consistent over a more extended time.In our meta-analysis, there was no significant different in terms of TLF when we compared the two groups at ≥ 5 years.These findings might have a substantial implication on stent selection in clinical practice, particularly in patients at high risk of late and very late stent failure and requires more clinical trials to evaluate the long-term effect of ultrathin stent struts.

Study limitations
This study has some limitations that affect the applicability of the study's conclusions.The absence of specific patient data from the chosen trials limits the use of advanced statistical techniques, including multivariable and subgroup analyses, which hinders the investigation of variations in the initial characteristics between groups of patients receiving DES.Despite these drawbacks, the research offers insightful information about the state of research on ACS.The open-label design of the included studies presents possible confounders.This absence of blinding could introduce a potential source of bias by influencing intravascular imaging guiding and vessel preparation techniques between DES treatment groups.Also, the meta-analysis design has some intrinsic limitations, such as the reliance on aggregate study-level data, which limits the comparison depth compared to patientlevel data.Patient-level analysis could enhance subgroup detection, providing a more nuanced understanding of the study outcomes.The SCAAR registry contributed to the large sample size of our study.This registry collected clinical data and procedural characteristics of all consecutive patients undergoing cardiac catheterization in Sweden, which may have influenced our overall results.

Conclusion
This meta-analysis showed the non-inferiority of ultrathin stent DES compared to standardized thickness DES regarding clinical outcomes such as all-cause mortality, cardiac mortality, MI, and probable or definite stent thrombosis.Additionally, ultrathin stent DES appears superior to the control group regarding TLF in short-term outcomes extending up to 3 years from PCI.
(1) bias due to confounding, (2) bias in the selection of participants into the study, (3) bias in the classification of interventions, (4) bias due to deviations from intended interventions, (5) bias due to missing data, bias in the measurement of outcomes, and (6) bias in the selection of the reported result.Any conflicts between the reviewers were resolved by consensus or consultation.

Fig. 1
Fig. 1 PRISMA flow diagram of the study

Fig. 5
Fig. 5 Forest plot of target vessel-related myocardial infarction (TVMI) from 1 to 5 years follow-up

Table 4
Summary of results analysis